Using Plasma Ceramides to Predict Coronary Artery Disease
Cardiovascular disease (CVD) is the number one cause of death globally, making improved prognostic disease indicators an urgent priority. Are ceramides a potential biomarker for our risk of CVD and coronary artery disease?
What are Ceramides?
Ceramides are complex bioactive membrane lipids produced in all cells. Found in high concentrations within the cell membrane, they are component lipids that make up sphingomyelin, one of the major lipids in the lipid bilayer.
In addition to their structural role, ceramides also act as a signaling molecule with multiple effects, including regulating differentiation, proliferation, and apoptosis.
The prognostic utility for ceramide as a biomarker for CVD is now also emerging.
Ceramide and Cholesterol Similarities
Ceramides share many similarities with cholesterol. Both are sticky, greasy molecules that are necessary for basic cell life, serving important structural roles in cellular membranes. Ceramides and cholesterol are also both intermediates in complex biosynthetic pathways that produce a host of complex lipid species.
Ceramides, like cholesterol, amass in atherosclerotic lesions and are abundant in plaques. As plasma ceramides are now readily quantifiable by mass spectrometry, the relationship between ceramides and cardiovascular death can be examined in stable and unstable coronary artery disease (CAD) patient populations. Risk assessments for primary and secondary myocardial infarction (MI) can also be performed.
Monitoring Ceramide Levels and Species to Predict Cardiovascular Events
Circulating ceramide levels strongly correlate with future adverse cardiovascular events, e.g., MI and stroke. In studies of patients with CAD, ceramides containing C16, C18, and C24:1 acyl chains displayed an independent predictive value of plaque instability. This predictive value went beyond that of conventional risk measures, including LDL cholesterol.
Ceramide species are produced by six fatty acyl selective ceramide synthases and it is becoming evident that individual ceramide species have specific physiological functions. Therefore monitoring ratios of ceramide species may provide insight into the metabolic regulation of atherosclerotic events.
The Ceramide Risk Score
In 2016, The Mayo Clinic launched a ceramide blood test for predicting adverse cardiovascular events in patients. Doctors are beginning to use ceramide levels as a predictive risk score to improve the identification of high-risk patients in need of more aggressive therapeutic interventions.
For example, in patients whose cholesterol goal is not met with traditional statin therapy and have increased ceramide risk scores, therapy may be more aggressive. This could include adding a PCSK9 inhibitor to a treatment regimen.
The ceramide risk score for predicting both primary and secondary events is independent and additive with LDL-C and CRP levels. Distinct plasma ceramide ratios are significant predictors of CV death both in patients with stable CAD and ACS, over and above currently-used lipid markers.
Ceramide Levels in Type 2 Diabetes
Of interest to diabetes researchers, elevated ceramide levels have been reported in the skeletal muscle of obese, insulin-resistant vs lean, insulin-sensitive men. Strong correlations were observed between muscle ceramide concentrations and insulin sensitivity with a wide cross-section of insulin sensitivity values.
Haus et al reported strong correlations between plasma concentrations of ceramide sub-species and both clamp-derived insulin sensitivity and plasma TNF-α concentrations in adults with and without type 2 diabetes.
Role of Ceramides in NAFLD
Ceramides signal the production of cytokines in a circular feedback loop. This is in response to increased pro-inflammatory cytokines, such as interleukin IL-1 and IL-6, which are present in NASH and correlate with augmented ceramide levels.
In the liver, ceramides interact with TNF-α and release reactive oxygen species (ROS), resulting in apoptosis and hepatic inflammation. Similarly, mice fed a high fat diet with subsequent steatosis displayed an increase in hepatic long chain ceramides (C16 and C18) which were associated with hepatocyte apoptosis.
The role of ceramides in NAFLD and lipotoxicity is still not fully understood and further investigations are needed.
Future of Ceramides
There are currnetly few prospective studies ongoing to determine whether elevated plasma ceramide concentrations predict coronary heart disease, mortality, or type 2 diabetes. Therefore the importance of plasma ceramides in terms of clinical endpoints is not known.
To date, there is no evidence in humans where manipulating ceramides therapeutically had a pathological role. There is some evidence in rodents suggesting that ablation of enzymes driving ceramide synthesis plays a causative role in metabolic pathologies. Further research is needed to investigate whether distinct plasma ceramides could be a useful therapeutic target for treatment and management of such metabolic pathologies in humans.
Beyond known key biomarkers, very few novel biomarkers have been consistent in predicting risk for either CVD or diabetes. For example, a common marker of inflammation (C-reactive protein), which is predictive of diabetes per se, does not replace risk prediction for diabetes beyond the typical clinical predictors (i.e. fasting glucose, triacylglycerol, BMI, and family history).
Nonetheless, it is encouraging that biomarkers to enhance the prediction of cardiovascular risk are being investigated, as any progress in CVD detection could significantly improve global lifespans.